Our overall objective is to elucidate the mechanisms that control formation of adipose tissues and to determine whether and how these processes might be harnessed to treat metabolic diseases. Modern life has provided unparalleled access to food supplies, contributing to a worldwide epidemic of obesity and secondary negative health consequences such as diabetes, fatty liver, cardiovascular disease, and even cancer. Thus there is an urgent need to better understand the mechanisms and molecules that control formation of adipocytes and the expansion of adipose tissue. Adipose tissue is highly dynamic, expanding and shrinking in response to various homeostatic, pharmacologic and dietary stimuli. That new adipocytes form throughout life indicates the presence of a putative adipogenic stem cell. Yet major barriers to unraveling the adipose stem cell compartment include lack of reagents, tools, and methods to study the adipose stem cell. Under the auspices of this award, we surmounted such issues, and identified the adipose stem cell by designing, engineering, and studying mice that express molecular reporters in the adipose lineage. These tools enable us to visualize adipose stem cells in vivo, to follow their descendents as they divide, migrate and develop into mature adipocytes, and to manipulate gene function with this key stem cell population. What's more, they allowed us to delineate the adipose stem cell niche, the specialized environment in which stem cells reside. The niche controls nearly all aspects of stem cell behavior, and therefore is a key target for new therapies. Indeed we found that the adipose stem cell niche is therpeutically accessible; these data uncovered a remarkable mechanistic advance that underlies this application. The central focus of this proposal is to use our tools to delineate the in vivo functions and molecular characteristics of developing and adult adipose stem cells, and our Preliminary Studies identify novel control mechanisms. We will define these mechanistic underpinnings of the adipose stem cells, we will understand how physiological and pharmacological stimuli regulate the stem population and the growth of adipose tissue, and we will exploit these insights to therapeutic ends. Our studies are designed to elucidate new aspects of adipose biology and metabolic control, highlighting those that are particularly relevant to new therapies for obesity and diabetes.